P583: PROGNOSTIC IMPLICATIONS OF WT1 MUTATIONS IN PATIENTS WITH DE NOVO AND RELAPSED ACUTE MYELOID LEUKEMIA IN THE ERA OF NOVEL TARGETED THERAPIES
Authors: Himachandana Atluri, Keyur Patel, Mark Routbort, Betul Oran, Ghayas Issa, Nicholas Short, Naval Daver, Tapan Kadia, Farhad Ravandi, Richard E. Champlin, Elizabeth J. Shpall, Sherry Pierce, Rashmi Kanagal-Shamanna, Chi Young Ok, Guilin Tang, Sa Wang, Rajyalakshmi Luthra, Audrey Lasrey, Bettina Nadorp, Antonia Chroni, Ann-Kathrin Eisfeld, Ioannis Aifantis, L. Jeffrey Medeiros, Courtney Dinardo, Sanam Loghavi
Journal: HemaSphere (2023)

Background: Wilms Tumor 1 (WT1) is integral to cell proliferation and survival in acute myeloid leukemia (AML). WT1 is mutated (WT1m) in 10-15% of patients (pts) with AML and is associated with poorer overall and relapse free-survival. WT1m frequently co-occur with mutations of fms-like 3 (FLT3m) and nucleophosmin 1 (NPM1m) and abrogate the favorable impact of NPM1m in pts treated with traditional high-intensity chemotherapy. The impact of WT1m in the setting of recently approved treatments for AML (e.g., venetoclax; VEN) remains unknown. Aims: We aim to describe the characteristics of WT1m AML in a large single institution pt cohort and to assess the impact of WT1m on the overall survival (OS) in pts treated with novel therapies with emphasis on co-mutated FLT3 and NPM1. Methods: We identified 304 pts with WT1m hematologic malignancies treated at our institution from 2017-2021. A clinical-grade next-generation sequencing panel was performed interrogating 81 recurrently mutated genes in myeloid neoplasms (limit of detection ~1-2%). Pts were stratified based on initial induction regimen and co-existing FLT3 m and/or NPM1 m. Measurable residual disease (MRD) was assessed using flow cytometry immunophenotyping (FCI; LOD 0.1-0.01%). Results: 218 of 304 pts had AML; 91 (42%) with WT1 m at baseline (de novo) and 127 (58%) with WT1 m mutations acquired at progression or relapse (R/R). The de novo cohort included 51 women and 40 men with a median age at diagnosis of 59 yrs (range, 24-81). Median OS was 25.2 mos (95% CI 17.2 – NA). 8 (9%) pts had NPM1 m/WT1 m without FLT3 (in 6/8 NPM1 m was clonally dominant) and median OS was not reached (NR) (p=0.09). 14 (15%) pts had FLT3 m(8 ITD, 3 TKD)/NPM1 m/WT1 m with median OS of 12.5 mos (95% CI 6.88 – NA, p=0.17). 30 (33%) pts had FLT3 m(14 ITD, 13 TKD)/WT1 m without NPM1 m with median OS of 59.1 mos (95% CI 19.4-NA, p=0.15). 45 (49%) pts were treated with intensive chemotherapy (IC) without VEN with a median OS of 38.0 mos with 19 (42%) in ongoing MRD negative complete response (CR). Among pts who received upfront IC + VEN (n=10; 11%), median OS was NR with 7 (70%) achieving MRD (-) CR. (Figure 1) 33 (36%) pts underwent hematopoietic stem cell transplant (HSCT); among these, 12 (33%) relapsed with persistent WT1 m clones. There was no difference in survival based on sex. The R/R cohort included 67 women and 60 men with a median age at diagnosis of 52 yrs (range, 13-83). Median OS was 23.1 mos (95% CI 19.9-26.4). 66 (52%) pts underwent HSCT of which 44 (67%) had post-transplant relapse with newly acquired WT1 m mutation. Median time to WT1 m acquisition was 12.1 mos with a median of 2 prior treatments. 8 pts (6%) had NPM1 m/WT1 m (WT1 m more commonly clonally dominant in 5 pts) and had a median OS of 38.7 mos (24.5 – NA, p=0.25). In 20 pts with FLT3 m (16 ITD, 3 TKD)/NPM1 m/WT1 m, median OS was 26.8 mos (95% CI 15 – 26.4, p = 0.15). 32 (23%) pts with FLT3 m (19 ITD/10 TKD)/WT1 m mutations had median OS of 18.7 mos (15-26.4, p =0.12). Only 2 pts received induction with IC + VEN. 93 (73%) pts received standard IC at time of diagnosis. 63 (50%) received VEN based therapy at some point after relapse. Median OS was 19.4 mos in pts who received VEN after relapse (95% CI 17.6 – 23.7) vs 24.8 mos (23.1-35.3, p=0.17) in those who did not receive VEN. All FLT3 mutated pts in both cohorts received FLT3i. Summary/Conclusion: Pts with co-mutated WT1/NPM1 without FLT3 had trends toward improved OS compared to pts with FLT3 or wild type NPM1 but the difference was not significant. Comparison to matched controls with NPM1 m/WT1 wild type pts is ongoing. Our data suggest that the addition of VEN and FLT3i based therapies contribute to improved OS in pts with de novo WT1m AML, however there is continued poor response to therapy in those with acquired WT1 m at relapse highlighting the need for novel therapeutic approaches in this group of AML pts.Keywords: WT1, Acute myeloid leukemia, Venetoclax, Post-transplant